We will establish the qualitative and quantitative potential of stem cells (SC) and committed progenitor cells of hematopoietic tissue (HSC) for the repair of damage to epithelial tissues. These studies are designed to examine the mechanisms responsible for tissue repair and regeneration. We believe in order to determine what regulates repair/regeneration we must show: a) What the factors are that induce conversion of hematopoietic stem cells into liver; b) what are the target cells responsible for the repair; c) how the cells can be delivered to the site of injury; d) how we can track the cells after transplantation; and e) what is the level of repair/regeneration over time. Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals. Thus our specific aims are: 1) we plan to determine the repair/regeneration potential of SC for repair of acutely or chronically injured liver. Further, we will examine the effect of injury signals on the conversion of HSC into functional cells of the injured tissue phenotype using a novel in vitro assay. Fusion is an additional mechanism which might be responsible for conversion. Therefore we will also study the consequences effusion if and when it occurs to understand this mechanism of cellular repair. Our in vitro studies will be complemented with in vivo transplant studies to determine the functional potential for SC therapy. Our aim 2) is to study which target cells can affect the repair of injured tissue. Is it possible that each tissue has its own reservoir of SC which can repair in particular circumstances? We will attempt to isolate SC from epithelial tissues by methods which we have already used to successfully isolated HSC and determine the potential for these cells to repair injured epithelial and hematopoietic tissue. Relevance Our long term goals of these studies are to utilize SC from hematopoietic and non-hematopoietic tissue to offer treatment options for diseases such as Diabetes, Cystic Fibrosis, as well as liver or kidney failure. Our plan is to establish the mechanisms which allow adult SC to reprogram in response to specific injury signals.